Children with seizures and radiological diagnosis of focal cortical dysplasia: can drug-resistant epilepsy be predicted earlier?

Objective: Focal cortical dysplasia (FCD) is a malformation of cortical development and is associated with drug-resistant epilepsy. Standard indication for epilepsy surgery is drug resistance (as defined by the ILAE). Given the high incidence of drug resistance in these children, this delay may not be warranted. The aim of the study was to determine the proportion of patients with a presumed FCD who develop drug resistance, and evaluate post-operative outcomes. Methods: This study incorporated a survey within a regional paediatric epilepsy network and a retrospective database review of a paediatric epilepsy center serving the network to identify children with epilepsy and a presumed FCD on MRI. Results: The survey revealed that 86% of the patients with epilepsy and presumed FCD on MRI within the network were referred to our centre. Of 139 pediatric patients included in the study, 131 (94.2%) had drug-resistant epilepsy. One hundred and ten (83.9%) patients were referred to epilepsy surgery, of whom 97 underwent surgery. Of 92 with one-year postoperative follow-up, 59.8% had an Engel Class 1 (seizure-free) outcome. Concordance of location between MRI and ictal EEG was strongly associated with Engel Class 1 outcome ( p <0.001), as was older age at seizure onset ( p =0.03). Time from diagnosis to surgery, number of medications, type of surgery and histology were not associated with improved outcome. Significance: Our data suggest that most children presenting with seizures and a radiological diagnosis of FCD will develop drug-resistant epilepsy and are candidates for epilepsy surgery. The main outcome predictors are the correlation between MRI and ictal EEG localization and age at onset. This suggests that patients with FCD and epilepsy may be considered for surgery before traditional criteria of drug resistance are met. This change in practice has the potential to improve quality of life and cognitive function, and reduce burden on epilepsy services

Lesion detection in epilepsy surgery: Lessons from a prospective evaluation of a machine learning algorithm

AIM: To evaluate a lesion detection algorithm designed to detect focal cortical dysplasia (FCD) in children undergoing stereoelectroencephalography (SEEG) as part of their presurgical evaluation for drug-resistant epilepsy. METHOD: This was a prospective, single-arm, interventional study (Idea, Development, Exploration, Assessment, and Long-Term Follow-Up phase 1/2a). After routine SEEG planning, structural magnetic resonance imaging sequences were run through an FCD lesion detection algorithm to identify putative clusters. If the top three clusters were not already sampled, up to three additional SEEG electrodes were added. The primary outcome measure was the proportion of patients who had additional electrode contacts in the SEEG-defined seizure-onset zone (SOZ). RESULTS: Twenty patients (median age 12 years, range 4-18 years) were enrolled, one of whom did not undergo SEEG. Additional electrode contacts were part of the SOZ in 1 out of 19 patients while 3 out of 19 patients had clusters that were part of the SOZ but they were already implanted. A total of 16 additional electrodes were implanted in nine patients and there were no adverse events from the additional electrodes. INTERPRETATION: We demonstrate early-stage prospective clinical validation of a machine learning lesion detection algorithm used to aid the identification of the SOZ in children undergoing SEEG. We share key lessons learnt from this evaluation and emphasize the importance of robust prospective evaluation before routine clinical adoption of such algorithms

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

Objective: We aimed to describe the extent of neurodevelopmental impairments andidentify the genetic etiologies in a large cohort of patients with epilepsy with myoclonicatonic seizures (MAE).Methods: We deeply phenotyped MAE patients for epilepsy features, intellectualdisability, autism spectrum disorder, and attention-deficit/hyperactivity disorderusing standardized neuropsychological instruments. We performed exome analysis(whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets toidentify genetic etiologies.Results: We analyzed 101 patients with MAE (70% male). The median age of seizureonset was 34 months (range = 6-72 months). The main seizure types were myoclonicatonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absencein 60%, and tonic seizures in 19% of patients. We observed intellectual disability in62% of patients, with extremely low adaptive behavioral scores in 69%. In addition,24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivitysymptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, includingfive previously published patients. These were pathogenic genetic variants inSYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2,SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three newcandidate genes, ASH1L, CHD4, and SMARCA2 in one patient each.Significance: MAE is associated with significant neurodevelopmental impairment.MAE is genetically heterogeneous, and we identified a pathogenic genetic etiologyin 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestationof several etiologies rather than a discrete syndromic entity

Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research

Clinical and molecular characterisation of KCNT1-related severe early onset epilepsy

Objective: To characterise the phenotypic spectrum, molecular genetic findings and functional consequences of pathogenic variants in early onset KCNT1-epilepsy. Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple gene next generation sequencing panel and whole exome sequencing. Additional patients with non-EIMFS early onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. Where possible, we performed homology modelling to predict putative effects of variants on protein structure and function. We undertook electrophysiological assessment of mutant KCNT1 channels in a Xenopus oocyte model system. Results: We identified pathogenic variants in KCNT1 in 12 patients, four of which are novel. Most variants occurred de novo. Ten had a clinical diagnosis of EIMFS and the other two presented with early onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in one. Computational modelling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain-of-function, with significantly increased channel amplitude and variable blockade by quinidine. Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, though clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy

Antiseizure medication reduction and withdrawal in children with drug-resistant epilepsy after starting the ketogenic diet

AIM: To investigate the rate of successful withdrawal of antiseizure medication (ASM) after starting the ketogenic diet in children and identify predictive factors. METHOD: We retrospectively reviewed data of children with epilepsy, who were treated with the ketogenic diet for 6 months or longer at our institution, over a 5-year period. We defined successful withdrawal of one or more medications as a time period of 3 months or more off this medication without restarting it or starting a new agent. Predictive clinical factors were investigated using binary multivariable logistic regression. RESULTS: Seventy-one children were included (28 females, 43 males; median age at seizure onset 5 months, median age at diet initiation 58.5 months, median duration of ketogenic diet 27.7 months). Reduction of one or more ASMs was attempted in 54 out of 71 (76%) children and was successful in 34 out of 54 (63%), including discontinuation of all ASMs in 13. Younger age at the start of the ketogenic diet was associated with higher odds of successful ASM withdrawal. ASM withdrawal was successful in 11 out of 19 children with less than 50% seizure reduction at 3 months. INTERPRETATION: Reduction of ASM was achieved in two-thirds of patients after the start of the ketogenic diet, where attempted, and can be successful even with little or unchanged seizure frequency while on the diet

Seizure outcome determinants in children after surgery for single unilateral lesions on MRI: role of preoperative ictal and interictal EEG

OBJECTIVE: To determine if an ictal EEG recording as part of pre-surgical evaluation of children with a demarcated single unilateral MRI lesion is indispensable for surgical decision making, we investigated the relationship between interictal/ ictal EEG and seizure semiology with seizure-free outcome. METHODS: Data were obtained retrospectively from consecutive patients (≤ 18 years) undergoing epilepsy surgery with a single unilateral MRI lesion at our institution over a 6-year period. Video-telemetry EEG (VT-EEG) was classified as concordant or non-concordant/non-informative in relation to the MRI lesion location. The odds of seizure-free outcome associated with non-concordant versus concordant for 'semiology', 'interictal' and 'ictal' EEG were compared separately. Multivariable logistic regression was conducted to correct for confounding variables. RESULTS: After a median follow-up of 26 months (IQR 17-37.5) 73 (69%) of 117 children enrolled were seizure free. Histopathological diagnoses included: low-grade epilepsy associated tumours 46 (39%), Focal Cortical Dysplasia (FCD) 33 (28%), mesial temporal sclerosis (MTS) 23 (20%), polymicrogyria 3, 3%) and non-diagnostic findings/gliosis 12 (10%). The odds of seizure freedom was lower with a non-concordant interictal EEG (OR=0.227, 95% CI 0.079 to 0.646, p=0.006) and non-concordant ictal EEG (OR=0.359, 95%CI 0.15 - 0.878, p=0.035). In the multivariable logistic regression model, factors predicting lower odds for seizure free outcome were developmental delay/intellectual disability, higher number of anti-seizure medications tried and a non-significant trend for 'non-concordant interictal EEG'. In the combined subgroup of patients with FCD and tumours (n=79) there was no significant relationship of VT-EEG factors and seizure outcomes, whilst in children with MTS and acquired lesions (n=25) a non- concordant EEG was associated with poorer seizure outcomes) p =0.003). SIGNIFICANCE: An ictal EEG may not be mandatory for pre-surgical evaluation, particularly when a well-defined single unilateral MRI lesion has been identified and the interictal EEG is concordant

Characterizing Frontal Lobe Seizure Semiology in Children

Objective: The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy. Methods: Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs &gt;4). Results:Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs 17.4%; p = 0.02) and contralateral head deviation (22.2% vs 0.0%; p = 0.03), ictal body-turning (55.6% vs 13.0%; p = 0.006; ipsilateral: 55.6% vs 4.3%; p = 0.0003), and complex motor signs (88.9% vs 56.5%; p = 0.037). Both age groups (≤4 and &gt;4 years) showed hyperkinetic features (21.1% vs 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs 3.6%; p = 0.005) and hypomotor features (31.6% vs 0.0%; p = 0.003), and fewer behavioral features (36.8% vs 71.4%; p = 0.03) and reduced responsiveness (31.6% vs 78.6%; p = 0.002). Interpretation: This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes. ANN NEUROL 2024.</p

Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES – Two different outcomes

Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one. This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used